Drug delivery compositions and medical devices containing block copolymer

ABSTRACT

A composition for delivery of a therapeutic agent is provided. The composition comprises: (a) a biocompatible block copolymer comprising one or more elastomeric blocks and one or more thermoplastic blocks and (b) a therapeutic agent, wherein the block copolymer is loaded with the therapeutic agent. The block copolymer is preferably of the formula X-(AB) n , where A is an elastomeric block, B is a thermoplastic block, n is a positive whole number and X is a seed molecule. The elastomeric blocks are preferably polyolefin blocks, and the thermoplastic blocks are preferably selected from vinyl aromatic blocks and methacrylate blocks. According to another aspect of the invention, a medical device is provided, at least a portion of which is insertable or implantable into the body of a patient. The medical device comprises (a) the above biocompatible block copolymer and (b) a therapeutic agent, wherein the block copolymer is loaded with the therapeutic agent. According to another aspect of the present invention, a method of treatment is provided in which the above device is implanted or inserted into a patient, resulting in the release of therapeutic agent in the patient over an extended period. According to yet another aspect of the invention, a coated medical device is provided which comprises: (a) an intravascular or intervascular medical device and (b) a coating over at least a portion of the intravascular or intervascular a medical device, wherein the coating comprises the above biocompatible block copolymer.

STATEMENT OF RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.11/057,870, filed Feb. 14, 2005, now U.S. Pat. No. 7,622,530, issuedNov. 24, 2009, which is a continuation of U.S. patent application Ser.No. 10/319,802 filed Dec. 13, 2002, now U.S. Pat. No. 6,855,770, issuedFeb. 15, 2005, which is a continuation of U.S. patent application Ser.No. 09/734,639, filed Dec. 12, 2000, now U.S. Pat. No. 6,545,097, issuedApr. 8, 2003, all of which are incorporated by reference herein in theirentireties.

FIELD OF THE INVENTION

The present invention relates to compositions for therapeutic agentdelivery comprising a therapeutic-agent-loaded block copolymer. Thepresent invention also relates to biocompatible block copolymermaterials for use in connection with intravascular or intervascularmedical devices.

BACKGROUND AND SUMMARY OF THE INVENTION

Polymers that release drug upon implantation or insertion into the bodyare known. However, a need remains in the art for a polymer that iseffective for drug-release, while at the same time having goodmechanical integrity and biocompatibility.

It is also known to use polymers in connection with implantable orinsertable medical devices. However, such polymers frequently elicit avigorous immune or foreign body response. This is particularly true ofintravascular or intervascular medical devices, which commonly sufferfrom the consequences of inflammation and neointimal thickening afterplacement within the vasculature.

The above and other needs in the prior art have been met by the presentinvention. According to one aspect of the invention, a composition fordelivery of a therapeutic agent is provided, which comprises: (a) abiocompatible block copolymer comprising one or more elastomeric blocksand one or more thermoplastic blocks and (b) a therapeutic agent,wherein the block copolymer is loaded with the therapeutic agent.

Numerous therapeutic agents are appropriate for use in connection withthe present invention including anti-thrombotic agents,anti-proliferative agents, anti-inflammatory agents, anti-migratoryagents, agents affecting extracellular matrix production andorganization, antineoplastic agents, anti-mitotic agents, anestheticagents, anti-coagulants, vascular cell growth promoters, vascular cellgrowth inhibitors, cholesterol-lowering agents, vasodilating agents,agents that interfere with endogenous vascoactive mechanisms, andcombinations thereof. One specific example of a therapeutic agent ispaclitaxel. The loaded block copolymer preferably comprises 0.1 to 70 wt% therapeutic agent.

Regarding the polymer configuration, the block copolymer is preferablyof the formula X-(AB)_(n), where A is an elastomeric block, B is athermoplastic block, n is a positive whole number and X is a seedmolecule.

Regarding the blocks within the copolymer, the elastomeric blocks arepreferably polyolefin blocks. More preferably, the polyolefin blocks areof the general formula —(CRR′—CH₂)_(n)—, where R and R′ are linear orbranched aliphatic groups or cyclic aliphatic groups. Even morepreferably, the polyolefin blocks are polyisobutylene blocks. The amountof polyolefin blocks preferably ranges from between 95 and 45 mol % ofthe block copolymer.

The thermoplastic blocks are preferably selected from vinyl aromaticblocks and methacrylate blocks. The methacrylate blocks are preferablyselected from methylmethacrylate, ethylmethacrylate and hydroxyethylmethacrylate monomers, as well as blocks of mixtures of these monomers.The vinyl aromatic polymer blocks are preferably selected from blocks ofstyrene and α-methylstyrene, as well as blocks of mixtures of thesemonomers.

The molecular weight of the block copolymer preferably ranges from80,000 to 300,000 Daltons. In some embodiments, the molecular weight ofthe polyolefin blocks preferably ranges from 60,000 to 200,000 Daltons,and the molecular weight of the vinyl aromatic polymer blocks preferablyranges from 20,000 to 100,000 Daltons.

According to another aspect of the present invention, a medical deviceis provided, at least a portion of which is insertable or implantableinto the body of a patient. The medical device comprises (a) the aboveblock copolymer and (b) a therapeutic agent, wherein the block copolymeris loaded with the therapeutic agent.

In some embodiments, only a portion of the medical device comprises theblock copolymer. As an example, the portion of the medical device can bein the form of a coating on the medical device. Preferred coatingdimensions are 0.1 to 50 microns in thickness.

Preferably, the therapeutic agent is released over an extended periodafter implantation in a patient.

Preferred sites for implantation or insertion of the medical device arethe coronary vasculature, peripheral vasculature, esophagus, trachea,colon, gastrointestinal tract, biliary tract, urinary tract, prostateand brain.

In some embodiments, the medical device is adapted such that at least aportion of the block copolymer is exposed to bodily fluid upon insertionor implantation in the body. In others, the medical device is adapted toexpose at least a portion of the block copolymer to tissue such as solidtissue.

Preferred medical devices include catheters, guide wires, balloons,filters, stents, stent grafts, vascular grafts, vascular patches, shuntsand intraluminal paving systems. In some embodiments, the medical deviceis provided with a sheath for covering the block copolymer duringinsertion into the body to prevent premature therapeutic agent release.

In certain embodiments, the medical device further comprises a polymeror copolymer of one or more of the following: a polycarboxylic acid, acellulose acetate polymer, a cellulose nitrate polymer, a gelatin, apolyvinylpyrrolidone, a cross-linked polyvinylpyrrolidone, apolyanhydride, a polyamide, a polyvinyl alcohol, a polyvinyl ether, apolyvinyl aromatic, a polyethylene oxide, a glycosaminoglycan, apolysaccharide, a polyester, a polyacrylamide, a polyether, a polyethersulfone, a polycarbonate, a polyalkylene, a halogenated polyalkylene, apolyurethane, a polyorthoester, a polypeptide, a silicone, a siloxanepolymer, a polylactic acid, a polyglycolic acid, a polycaprolactone, apolyhydroxybutyrate valerate, a fibrin, a collagen, a collagenderivative or a hyaluronic acid. Particularly preferred polymers andcopolymers are polyacrylic acids, ethylene-vinyl acetate copolymers, andcopolymers of polylactic acid and polycaprolactone.

Such polymers or copolymers can be blended with the biocompatible blockcopolymer, or they can be provided in a layer that does not contain thebiocompatible block copolymer.

According to another aspect of the present invention, a method oftreatment is provided in which the above device is implanted or insertedinto a patient, resulting in the release of therapeutic agent in thepatient over an extended period of time.

According to yet another aspect of the invention, a coated medicaldevice is provided which comprises: (a) an intravascular orintervascular medical device; and (b) a coating over at least a portionof the intravascular or intervascular medical device, the coatingcomprising the above biocompatible block copolymer. Preferredintravascular or intervascular medical devices for this aspect of theinvention include balloons, stents, stent grafts, vascular grafts,vascular patches, shunts, catheters and filters.

One advantage of the present invention is that it provides apolymer-based drug delivery composition with good mechanical integrity.

Another advantage is that a polymer-based drug delivery composition canbe provided that has good biocompatibility.

Another advantage of the present invention is that medical devices canbe provided that, upon placement in the vasculature, result in reducedinflammation and neointimal thickening relative to other traditionallyused polymeric materials.

Still other embodiments and advantages will become readily apparent tothose skilled in the art upon review of the Specification and Claims tofollow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates release rate as a function of time for stents coatedwith polystyrene-polyisobutylene-polystyrene copolymer and paclitaxel invarying ratios.

FIGS. 2A-2D are photographs, after 28 days in a porcine coronary artery,of (1) a bare stainless steel stent, (2) a stainless steel stent with acoating of traditional “biostable” polyurethane polymer, (3) a stainlesssteel stent with a coating of a traditional “biodegradable” copolymer ofpolylactic acid (“PLA”) and polycaprolactone (“PCL”) and (4) a stainlesssteel stent covered with a coating ofpolystyrene-polyisobutylene-polystyrene copolymer in accordance with anembodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compositions comprising atherapeutic-agent-loaded block copolymer that are useful for delivery ofa therapeutic agent and to biocompatible block copolymer materialsuseful, for example, in connection with intravascular or intervascularmedical devices.

Block copolymers suitable for the practice of the present inventionpreferably have a first elastomeric block and a second thermoplasticblock. More preferably, the block copolymers have a central elastomericblock and thermoplastic end blocks. Even more preferably, such blockcopolymers have the general structure:

-   -   (a) BAB or ABA (linear triblock),    -   (b) B(AB)_(n) or A(BA)_(n) (linear alternating block), or    -   (c) X-(AB)_(n) or X-(BA)_(n) (includes diblock, triblock and        other radial block copolymers),        where A is an elastomeric block, B is a thermoplastic block, n        is a positive whole number and X is a starting seed molecule.

Most preferred are X-(AB)_(n) structures, which are frequently referredto as diblock copolymers and triblock copolymers where n=1 and n=2,respectively (this terminology disregards the presence of the startingseed molecule, for example, treating A-X-A as a single A block with thetriblock therefore denoted as BAB). Where n=3 or more, these structuresare commonly referred to as star-shaped block copolymers.

The A blocks are preferably soft elastomeric components which are basedupon one or more polyolefins, more preferably a polyolefinic blockhaving alternating quaternary and secondary carbons of the generalformulation: —(CRR′—CH₂)_(n)—, where R and R′ are linear or branchedaliphatic groups such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl and so forth, or cyclic aliphatic groups such as cyclohexane,cyclopentane, and the like, with and without pendant groups.

Polymers of isobutylene,

(i.e., polymers where R and R′ are the same and are methyl groups) aremost preferred.

The B blocks are preferably hard thermoplastic blocks that, whencombined with the soft A blocks, are capable of, inter alia, altering oradjusting the hardness of the resulting copolymer to achieve a desiredcombination of qualities. Preferred B blocks are polymers ofmethacrylates or polymers of vinyl aromatics. More preferred B blocksare (a) made from monomers of styrene

styrene derivatives (e.g., α-methylstyrene, ring-alkylated styrenes orring-halogenated styrenes) or mixtures of the same or are (b) made frommonomers of methylmethacrylate, ethylmethacrylate hydroxyethylmethacrylate or mixtures of the same.

The properties of the block copolymers used in connection with thepresent invention will depend upon the lengths of the A blocks and Bblocks, as well as the relative amounts of each.

For example, the elastomeric properties of the block copolymer willdepend on the length of the A block chains, with a weight averagemolecular weight of from about 2,000 to about 30,000 Daltons tending toproduce rather inelastic products, and a weight average molecular weightof 40,000 Daltons or above tending to produce products that are moresoft and rubbery. Hence, for purposes of the present invention, thecombined molecular weight of the block copolymer is preferably in excessof 40,000 Daltons, more preferably in excess of 60,000 Daltons, and mostpreferably between about 90,000 to about 300,000 Daltons.

As another example, the hardness of the block copolymer is proportionalto the relative amount of B blocks. In general, the copolymer has apreferred hardness that is between about Shore 20 A and Shore 75 D, andmore preferably between about Shore 40 A and Shore 90 A. This result canbe achieved by varying the proportions of the A and B blocks, with alower relative proportion of B blocks resulting in a copolymer of lowerhardness, and a higher relative proportion of B blocks resulting in acopolymer of higher hardness. As a specific example, high molecularweight (i.e., greater than 100,000 Daltons) polyisobutylene is a softgummy material with a Shore hardness of approximately 10 A. Polystyrene,is much harder, typically having a Shore hardness on the order of 100 D.As a result, when blocks of polyisobutylene and styrene are combined,the resulting copolymer can have a range of hardnesses from as soft asShore 10 A to as hard as Shore 100 D, depending upon the relativeamounts of polystyrene and polyisobutylene. In general, to achieve apreferred hardness ranging from Shore 30 A to Shore 90 A, the amount ofpolystyrene ranges from between 2 and 25 mol %. More preferably, thepreferred hardness ranges from Shore 35 A to Shore 70 A and the amountof polystyrene ranges from 5 to 20 mol %.

Polydispersity (i.e., the ratio of weight average molecular weight tonumber average molecular weight) gives an indication of the molecularweight distribution of the copolymer, with values significantly greaterthan 4 indicating a broad molecular weight distribution. Thepolydispersity has a value of one when all molecules within a sample arethe same size. Typically, the copolymers for use in connection with thepresent invention have a relatively tight molecular weight distribution,with a polydispersity of about 1.1 to 1.7.

One advantage associated with the above-described copolymers is theirhigh tensile strength. For example, the tensile strength of triblockcopolymers of polystyrene-polyisobutylene-polystyrene frequently rangesfrom 2,000 to 4,000 psi or more.

Another advantage of such copolymers is their resistance to cracking andother forms of degradation under in vivo conditions. In addition, thesepolymers exhibit excellent biocompatibility, including vascularcompatibility, as demonstrated by their tendency to provoke minimaladverse tissue reactions as demonstrated by reduced polymorphonuclearleukocyte and reduced macrophage activity. Still further, these polymersare generally hemocompatible as demonstrated by their ability tominimize thrombotic occlusion of small vessels as demonstrated bycoating such copolymers on coronary stents. See Example 6 below.

The above-described block copolymers can be made using any appropriatemethod known in the art. A preferred process of making the blockcopolymers is by carbocationic polymerization involving an initialpolymerization of a monomer or mixtures of monomers to form the Ablocks, followed by the subsequent addition of a monomer or a mixture ofmonomers capable of forming the B blocks.

Such polymerization reactions can be found, for example, in AdditionalU.S. Pat. Nos. 4,276,394, 4,316,973, 4,342,849, 4,910,321, 4,929,683,4,946,899, 5,066,730, 5,122,572 and/or Re. 34,640. Each of these patentsis hereby incorporated by reference in its entirety.

The techniques disclosed in these patents generally involve a “catalyststarting molecule” (also referred to as “initiators”, “telechelicstarting molecules”, “seed molecules” or “infers”), which can be used tocreate X-(AB)_(n) structures, where X is the catalyst starting molecule,and n can be 1, 2, 3 or more. As noted above, the resulting moleculesare referred to as diblock copolymers where n is 1, triblock copolymers(disregarding the presence of the starting molecule) where n is 2, andstar-shaped block copolymers where n is 3 or more.

In general, the polymerization reaction is conducted under conditionsthat minimize or avoid chain transfer and termination of the growingpolymer chains. Steps are taken to keep active hydrogen atoms (water,alcohol and the like) to a minimum. The temperature for thepolymerization is usually between −10° and −90° C., the preferred rangebeing between −60° and −80° C., although lower temperatures may beemployed if desired.

Preferably, one or more A blocks, for example, polyisobutylene blocks,are formed in a first step, followed by the addition of B blocks, forexample, polystyrene blocks, at the ends of the A blocks.

More particularly, the first polymerization step is generally carriedout in an appropriate solvent system, typically a mixture of polar andnon-polar solvents such as methyl chloride and hexanes. The reactionbath typically contains:

-   -   the aforementioned solvent system,    -   olefin monomer, such as isobutylene,    -   an initiator (inifer or seed molecule) such as tert-ester,        tert-ether, tert-hydroxyl or tert-halogen containing compounds,        and more typically cumyl esters of hydrocarbon acids, alkyl        cumyl ethers, cumyl halides and cumyl hydroxyl compounds as well        as hindered versions of the above,    -   a coinitiator, typically a Lewis Acid, such as boron trichloride        or titanium tetrachloride.

Electron pair donors such as dimethyl acetamide, dimethyl sulfoxide, ordimethyl phthalate can be added to the solvent system. Additionally,proton-scavengers that scavenge water, such as2,6-di-tert-butylpyridine, 4-methyl-2,6-di-tert-butylpyridine,1,8-bis(dimethylamino)-naphthalene, or diisopropylethyl amine can beadded.

The reaction is commenced by removing the tert-ester, tert-ether,tert-hydroxyl or tert-halogen (herein called the “tert-leaving groups”)from the seed molecule by reacting it with the Lewis acid. In place ofthe tert-leaving groups is a quasi-stable or “living” cation which isstabilized by the surrounding tertiary carbons as well as the polarsolvent system and electron pair donors. After obtaining the cation, theA block monomer, such as isobutylene, is introduced which cationicallypropagates or polymerizes from each cation on the seed molecule. Whenthe A block is polymerized, the propagated cations remain on the ends ofthe A blocks. The B block monomer, such as styrene, is then introducedwhich polymerizes and propagates from the ends of the A block. Once theB blocks are polymerized, the reaction is terminated by adding atermination molecule such as methanol, water and the like.

As is normally the case, product molecular weights are determined byreaction time, reaction temperature, the nature and concentration of thereactants, and so forth. Consequently, different reaction conditionswill produce different products. In general, synthesis of the desiredreaction product is achieved by an iterative process in which the courseof the reaction is monitored by the examination of samples takenperiodically during the reaction—a technique widely employed in the art.To achieve the desired product, an additional reaction may be requiredin which reaction time and temperature, reactant concentration, and soforth are changed.

Additional details regarding cationic processes for making copolymersare found, for example, in U.S. Pat. Nos. 4,276,394, 4,316,973,4,342,849, 4,910,321, 4,929,683, 4,946,899, 5,066,730, 5,122,572 and/orRe. 34,640.

The block copolymers described in the preceding paragraphs may berecovered from the reaction mixtures by any of the usual techniquesincluding evaporation of solvent, precipitation with a non-solvent suchas an alcohol or alcohol/acetone mixture, followed by drying, and soforth. In addition, purification of the copolymer can be performed bysequential extraction in aqueous media, both with and without thepresence of various alcohols, ethers and ketones.

Once synthesized, the block copolymers can be used, for example, toprovide therapeutic-agent-loaded block copolymer compositions fortherapeutic agent delivery, or to provide biocompatible intravascular orintervascular devices.

For a given mode of administration, a wide variety of therapeuticagents, including genetic therapeutic agents, non-genetic therapeuticagents, and cells, can be used in conjunction with the block copolymersof the invention.

Exemplary non-genetic therapeutic agents include:

-   -   anti-thrombotic agents such as heparin, heparin derivatives,        urokinase, and PPack (dextrophenylalanine proline arginine        chloromethylketone);    -   anti-inflammatory agents such as dexamethasone, prednisolone,        corticosterone, budesonide, estrogen, sulfasalazine and        mesalamine;    -   antineoplastic/antiproliferative/anti-miotic agents such as        paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,        epothilones, endostatin, angiostatin, angiopeptin, monoclonal        antibodies capable of blocking smooth muscle cell proliferation,        and thymidine kinase inhibitors;    -   anesthetic agents such as lidocaine, bupivacaine and        ropivacaine;    -   anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an        RGD peptide-containing compound, heparin, hirudin, antithrombin        compounds, platelet receptor antagonists, anti-thrombin        antibodies, anti-platelet receptor antibodies, aspirin,        prostaglandin inhibitors, platelet inhibitors and tick        antiplatelet peptides;    -   vascular cell growth promoters such as growth factors,        transcriptional activators, and translational promotors;    -   vascular cell growth inhibitors such as growth factor        inhibitors, growth factor receptor antagonists, transcriptional        repressors, translational repressors, replication inhibitors,        inhibitory antibodies, antibodies directed against growth        factors, bifunctional molecules consisting of a growth factor        and a cytotoxin, bifunctional molecules consisting of an        antibody and a cytotoxin;    -   protein kinase and tyrosine kinase inhibitors (e.g.,        tyrphostins, genistein, quinoxalines);    -   prostacyclin analogs;    -   cholesterol-lowering agents;    -   angiopoietins;    -   antimicrobial agents such as triclosan, cephalosporins,        aminoglycosides and nitrofurantoin;    -   cytotoxic agents, cytostatic agents and cell proliferation        affectors;    -   vasodilating agents; and    -   agents that interfere with endogenous vascoactive mechanisms.

Exemplary genetic therapeutic agents include:

-   -   anti-sense DNA and RNA;    -   DNA coding for:        -   anti-sense RNA,        -   tRNA or rRNA to replace defective or deficient endogenous            molecules,        -   angiogenic factors including growth factors such as acidic            and basic fibroblast growth factors, vascular endothelial            growth factor, epidermal growth factor, transforming growth            factor α and β, platelet-derived endothelial growth factor,            platelet-derived growth factor, tumor necrosis factor α,            hepatocyte growth factor and insulin like growth factor,        -   cell cycle inhibitors including CD inhibitors,        -   thymidine kinase (“TK”) and other agents useful for            interfering with cell proliferation, and        -   the family of bone morphogenic proteins (“BMP's”), including            BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1),            BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14,            BMP-15, and BMP-16. Currently preferred BMP's are any of            BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7. These dimeric            proteins can be provided as homodimers, heterodimers, or            combinations thereof, alone or together with other            molecules. Alternatively or, in addition, molecules capable            of inducing an upstream or downstream effect of a BMP can be            provided. Such molecules include any of the “hedgehog”            proteins, or the DNA's encoding them.    -   Vectors of interest for delivery of genetic therapeutic agents        include        -   Plasmids        -   Viral vectors such as adenovirus (AV), adenoassociated virus            (AAV) and lentivirus        -   Non-viral vectors such as lipids, liposomes and cationic            lipids.

Cells include cells of human origin (autologous or allogeneic),including stem cells, or from an animal source (xenogeneic), which canbe genetically engineered if desired to deliver proteins of interest.

Several of the above and numerous additional therapeutic agentsappropriate for the practice of the present invention are disclosed inU.S. Pat. No. 5,733,925 assigned to NeoRx Corporation, the entiredisclosure of which is incorporated by reference. Therapeutic agentsdisclosed in this patent include the following:

“Cytostatic agents” (i.e., agents that prevent or delay cell division inproliferating cells, for example, by inhibiting replication of DNA or byinhibiting spindle fiber formation). Representative examples ofcytostatic agents include modified toxins, methotrexate, adriamycin,radionuclides (e.g., such as disclosed in Fritzberg et al., U.S. Pat.No. 4,897,255), protein kinase inhibitors, including staurosporin, aprotein kinase C inhibitor of the following formula,

as well as diindoloalkaloids having one of the following generalstructures:

as well as stimulators of the production or activation of TGF-beta,including tamoxifen and derivatives of functional equivalents (e.g.,plasmin, heparin, compounds capable of reducing the level orinactivating the lipoprotein Lp(a) or the glycoproteinapolipoprotein(a)) thereof, TGF-beta or functional equivalents,derivatives or analogs thereof, suramin, nitric oxide releasingcompounds (e.g., nitroglycerin) or analogs or functional equivalentsthereof, paclitaxel or analogs thereof (e.g., taxotere), inhibitors ofspecific enzymes (such as the nuclear enzyme DNA topoisomerase II andDNA polymerase, RNA polymerase, adenyl guanyl cyclase), superoxidedismutase inhibitors, terminal deoxynucleotidyl-transferase, reversetranscriptase, antisense oligonucleotides that suppress smooth musclecell proliferation and the like.

Other examples of “cytostatic agents” include peptidic or mimeticinhibitors (i.e., antagonists, agonists, or competitive ornon-competitive inhibitors) of cellular factors that may (e.g., in thepresence of extracellular matrix) trigger proliferation of smooth musclecells or pericytes: e.g., cytokines (e.g., interleukins such as IL-1),growth factors (e.g., PDGF, TGF-alpha or -beta, tumor necrosis factor,smooth muscle- and endothelial-derived growth factors, i.e., endothelin,FGF), homing receptors (e.g., for platelets or leukocytes), andextracellular matrix receptors (e.g., integrins). Representativeexamples of useful therapeutic agents in this category of cytostaticagents addressing smooth muscle proliferation include: subfragments ofheparin, triazolopyrimidine (trapidil; a PDGF antagonist), lovastatin,and prostaglandins E1 or I2.

Agents that inhibit migration of vascular smooth muscle cells from themedial wall into the intima (“anti-migratory agents”). Several preferredexamples are derived from phenylalanine (cytochalasins), tryptophan(chaetoglobosins), or leucine (aspochalasins), resulting in a benzyl,indol-3-yl methyl or isobutyl group, respectively, at position C-3 of asubstituted perhydroisoindole-1-one moiety (Formula V or VI).

The perhydroisoindole moiety in turn contains an 11-, 13- or 14-atomcarbocyclic- or oxygen-containing ring linked to positions C-8 and C-9.All naturally occurring cytochalasins contain a methyl group at C-5; amethyl or methylene group at C-12; and a methyl group at C-14 or C-16.Exemplary molecules include cytochalasin A, cytochalasin B, cytochalasinC, cytochalasin D, cytochalasin E, cytochalasin F, cytochalasin G,cytochalasin H, cytochalasin J, cytochalasin K, cytochalasin L,cytochalasin M, cytochalasin N, cytochalasin O, cytochalasin P,cytochalasin Q, cytochalasin R, cytochalasin S, chaetoglobosin A,chaetoglobosin B, chaetoglobosin C, chaetoglobosin D, chaetoglobosin E,chaetoglobosin F, chaetoglobosin J, chaetoglobosin K, deoxaphomin,proxiphomin, protophomin, zygosporin D, zygosporin E, zygosporin F,zygosporin G, aspochalasin B, aspochalasin C, aspochalasin D and thelike, as well as functional equivalents and derivatives thereof. Certaincytochalasin derivatives are set forth in Japanese Patent Nos. 7201,925; 72 14,219; 72 08,533; 72 23,394; 72 01924; and 72 04,164.

Other representative examples of anti-migratory agents includeinhibitors (i.e., agonists and antagonists, and competitive ornon-competitive inhibitors) of chemotactic factors and their receptors(e.g., complement chemotaxins such as C5a, C5a desarg or C4a;extracellular matrix factors, e.g., collagen degradation fragments), orof intracellular cytoskeletal proteins involved in locomotion (e.g.,actin, cytoskeletal elements, and phosphatases and kinases involved inlocomotion). Representative examples of useful therapeutic agents inthis category of anti-migratory agents include: caffeic acid derivativesand nilvadipine (a calcium antagonist), and steroid hormones.

Agents that inhibit the intracellular increase in cell volume (i.e., thetissue volume occupied by a cell) such as cytoskeletal inhibitors ormetabolic inhibitors. Representative examples of cytoskeletal inhibitorsinclude colchicine, vinblastin, cytochalasins, paclitaxel and the like,which act on microtubule and microfilament networks within a cell.Representative examples of metabolic inhibitors include staurosporin,trichothecenes, and modified diphtheria and ricin toxins, Pseudomonasexotoxin and the like. Trichothecenes include simple trichothecenes(i.e., those that have only a central sesquiterpenoid structure) andmacrocyclic trichothecenes (i.e., those that have an additionalmacrocyclic ring), e.g., a verrucarins or roridins, including VerrucarinA, Verrucarin B, Verrucarin J (Satratoxin C), Roridin A, Roridin C,Roridin D, Roridin E (Satratoxin D), Roridin H.

Agents acting as an inhibitor that blocks cellular protein synthesisand/or secretion or organization of extracellular matrix (i.e., an“anti-matrix agent”). Representative examples of “anti-matrix agents”include inhibitors (i.e., agonists and antagonists and competitive andnon-competitive inhibitors) of matrix synthesis, secretion and assembly,organizational cross-linking (e.g., transglutaminases cross-linkingcollagen), and matrix remodeling (e.g., following wound healing). Arepresentative example of a useful therapeutic agent in this category ofanti-matrix agents is colchicine, an inhibitor of secretion ofextracellular matrix. Another example is tamoxifen for which evidenceexists regarding its capability to organize and/or stabilize as well asdiminish smooth muscle cell proliferation following angioplasty. Theorganization or stabilization may stem from the blockage of vascularsmooth muscle cell maturation in to a pathologically proliferating form.

Agents that are cytotoxic to cells, particularly cancer cells. Preferredagents are Roridin A, Pseudomonas exotoxin and the like or analogs orfunctional equivalents thereof. A plethora of such therapeutic agents,including radioisotopes and the like, have been identified and are knownin the art. In addition, protocols for the identification of cytotoxicmoieties are known and employed routinely in the art.

A number of the above therapeutic agents and several others have alsobeen identified as candidates for vascular treatment regimens, forexample, as agents targeting restenosis. Such agents are appropriate forthe practice of the present invention and include one or more of thefollowing:

-   -   Ca-channel blockers including:        -   Benzothiazapines such as diltiazem and clentiazem        -   Dihydropyridines such as nifedipine, amlodipine and            nicardapine        -   Phenylalkylamines such as verapamil    -   Serotonin pathway modulators including:        -   5-HT antagonists such as ketanserin and naftidrofuryl        -   5-HT uptake inhibitors such as fluoxetine    -   Cyclic nucleotide pathway agents including:        -   Phosphodiesterase inhibitors such as cilostazole and            dipyridamole        -   Adenylate/Guanylate cyclase stimulants such as forskolin        -   Adenosine analogs    -   Catecholamine modulators including:        -   α-antagonists such as prazosin and bunazosine        -   β-antagonists such as propranolol        -   α/β-antagonists such as labetalol and carvedilol    -   Endothelin receptor antagonists    -   Nitric oxide donors/releasing molecules including:        -   Organic nitrates/nitrites such as nitroglycerin, isosorbide            dinitrate and amyl nitrite        -   Inorganic nitroso compounds such as sodium nitroprusside        -   Sydnonimines such as molsidomine and linsidomine        -   Nonoates such as diazenium diolates and NO adducts of            alkanediamines        -   S-nitroso compounds including low molecular weight compounds            (e.g., S-nitroso derivatives of captopril, glutathione and            N-acetyl penicillamine), high molecular weight compounds            (e.g., S-nitroso derivatives of proteins, peptides,            oligosaccharides, polysaccharides, synthetic            polymers/oligomers and natural polymers/oligomers)        -   C-nitroso-, O-nitroso- and N-nitroso-compounds        -   L-arginine    -   ACE inhibitors such as cilazapril, fosinopril and enalapril    -   ATII-receptor antagonists such as saralasin and losartin    -   Platelet adhesion inhibitors such as albumin and polyethylene        oxide    -   Platelet aggregation inhibitors including:        -   Aspirin and thienopyridine (ticlopidine, clopidogrel)        -   GP IIb/IIIa inhibitors such as abciximab, epitifibatide and            tirofiban    -   Coagulation pathway modulators including:        -   Heparinoids such as heparin, low molecular weight heparin,            dextran sulfate and β-cyclodextrin tetradecasulfate        -   Thrombin inhibitors such as hirudin, hirulog,            PPACK(D-phe-L-propyl-L-arg-chloromethylketone) and            argatroban        -   FXa inhibitors such as antistatin and TAP (tick            anticoagulant peptide)        -   Vitamin K inhibitors such as warfarin        -   Activated protein C    -   Cyclooxygenase pathway inhibitors such as aspirin, ibuprofen,        flurbiprofen, indomethacin and sulfinpyrazone    -   Natural and synthetic corticosteroids such as dexamethasone,        prednisolone, methprednisolone and hydrocortisone    -   Lipoxygenase pathway inhibitors such as nordihydroguairetic acid        and caffeic acid    -   Leukotriene receptor antagonists    -   Antagonists of E- and P-selectins    -   Inhibitors of VCAM-1 and ICAM-1 interactions    -   Prostaglandins and analogs thereof including:        -   Prostaglandins such as PGE1 and PGI2        -   Prostacyclin analogs such as ciprostene, epoprostenol,            carbacyclin, iloprost and beraprost    -   Macrophage activation preventers including bisphosphonates    -   HMG-CoA reductase inhibitors such as lovastatin, pravastatin,        fluvastatin, simvastatin and cerivastatin    -   Fish oils and omega-3-fatty acids    -   Free-radical scavengers/antioxidants such as probucol, vitamins        C and E, ebselen, trans-retinoic acid and SOD mimics    -   Agents affecting various growth factors including:        -   FGF pathway agents such as bFGF antibodies and chimeric            fusion proteins        -   PDGF receptor antagonists such as trapidil        -   IGF pathway agents including somatostatin analogs such as            angiopeptin and ocreotide        -   TGF-β pathway agents such as polyanionic agents (heparin,            fucoidin), decorin, and TGF-β antibodies        -   EGF pathway agents such as EGF antibodies, receptor            antagonists and chimeric fusion proteins        -   TNF-α pathway agents such as thalidomide and analogs thereof        -   Thromboxane A2 (TXA2) pathway modulators such as sulotroban,            vapiprost, dazoxiben and ridogrel        -   Protein tyrosine kinase inhibitors such as tyrphostin,            genistein and quinoxaline derivatives    -   MMP pathway inhibitors such as marimastat, ilomastat and        metastat    -   Cell motility inhibitors such as cytochalasin B    -   Antiproliferative/antineoplastic agents including:        -   Antimetabolites such as purine analogs(6-mercaptopurine),            pyrimidine analogs (e.g., cytarabine and 5-fluorouracil) and            methotrexate        -   Nitrogen mustards, alkyl sulfonates, ethylenimines,            antibiotics (e.g., daunorubicin, doxorubicin), nitrosoureas            and cisplatin        -   Agents affecting microtubule dynamics (e.g., vinblastine,            vincristine, colchicine, paclitaxel and epothilone)        -   Caspase activators        -   Proteasome inhibitors        -   Angiogenesis inhibitors (e.g., endostatin, angiostatin and            squalamine)        -   Rapamycin, cerivastatin, flavopiridol and suramin    -   Matrix deposition/organization pathway inhibitors such as        halofuginone or other quinazolinone derivatives and tranilast    -   Endothelialization facilitators such as VEGF and RGD peptide    -   Blood rheology modulators such as pentoxifylline.

In addition, combinations of the above therapeutic agents can be used.

A wide range of therapeutic agent loadings can be used in connectionwith the above block copolymers, with the amount of loading beingreadily determined by those of ordinary skill in the art and ultimatelydepending upon the condition to be treated, the nature of thetherapeutic agent itself, the means by which thetherapeutic-agent-loaded copolymer is administered to the intendedsubject, and so forth. The loaded copolymer will frequently comprisefrom less than one to 70 wt % therapeutic agent.

In many preferred embodiments of the invention, the copolymer is used toprovide (a) the entirety of a medical device or (b) a portion of amedical device (i.e., the copolymer is used as a “device or deviceportion”). Portions of medical devices for which the copolymers of thepresent invention find use include any fraction of a medical device,such as device coatings, device components and so forth.

In some instances, therapeutic agent is released from the device ordevice portion to a bodily tissue or bodily fluid upon contacting thesame. An extended period of release (i.e., 50% release or less over aperiod of 24 hours) may be preferred in some cases.

In other instances, for example, in the case where enzymes, cells andother agents capable of acting on a substrate are used as a therapeuticagent, the therapeutic agent may remain within a copolymer matrix.

Preferred medical devices for use in conjunction with the presentinvention include catheters, preferably vascular catheters and morepreferably balloon catheters, guide wires, balloons, filters (e.g., venacava filters), vascular stents (including covered stents such as PTFE(polytetrafluoroethylene)-covered stents), stent grafts, cerebralstents, cerebral aneurysm filler coils (including GDC (Guglilmidetachable coils) and metal coils), vascular grafts, myocardial plugs,pacemaker leads, heart valves and intraluminal paving systems. Examplesof stents include NIR stents, Medinol, Israel, RADIUS stents, ScimedLife Systems, Maple Grove, Minn., WALLSTENT stents, Boston Scientific,Natick, Mass. and SYMPHONY stents, Boston Scientific Corp., Natick,Mass. The copolymers of the present invention can also be used incomposites for aneurysm fillers (e.g. polymeric mixtures of copolymerwith alginates, cyanoacrylates, hydrophilic polymers and so forth). Thecopolymers of the present invention are further useful to incorporatecells for cell therapy and are useful for tissue engineeringapplications (e.g., as scaffolds for cell delivery in cardiacapplications, liver regeneration, and so forth).

As noted above, the copolymer can comprise the entire device or aportion of the device, including a coating on the device or a componentof a device, and so forth.

Medical devices comprising a therapeutic-agent-loaded copolymer deviceor device portion in accordance with the present invention can be placedin a wide variety of bodily locations for contact with bodily tissue orfluid. Some preferred placement locations include the coronaryvasculature or peripheral vascular system (referred to collectivelyherein as the vasculature), esophagus, trachea, colon, biliary tract,urinary tract, prostate and brain.

In some instances, it may be desirable to temporarily enclose thetherapeutic-agent-loaded copolymer to prevent release before the medicaldevice reaches its ultimate placement site. As a specific example, astent or catheter comprising therapeutic-agent-loaded copolymer can becovered with a sheath during insertion into the body to preventpremature therapeutic agent release.

Numerous techniques are available for creating medical devices anddevice portions from the block copolymers described herein.

For example, the fact that the block copolymers have thermoplasticcharacter opens up a variety of standard thermoplastic processingtechniques for device and device portion formation, includingcompression molding, injection molding, blow molding, spinning, vacuumforming and calendaring, as well as extrusion into sheets, fibers, rods,tubes and other cross-sectional profiles of various lengths. Using theseand other techniques, devices such as balloons, catheters, stents andportions of devices can be made from the block copolymers.

Assuming that the therapeutic agent to be loaded is stable at processingtemperatures, then it can be combined with the copolymer by extrusionprior to thermoplastic processing, producing a therapeutic-agent-loadeddevice or device portion. Otherwise, the therapeutic agent can be loadedafter formation of the device or device portion as discussed below.

Devices or device portions can also be made using solvent-basedtechniques in which the block copolymer is first dissolved in a solventand the block-copolymer solution is subsequently used to form the deviceor device portion. The solvent should, of course, be compatible with theblock copolymer. As an example, compatible solvents for block copolymersof styrene and isobutylene include tetrahydrofuran, toluene, xylene,hexanes, heptanes, combinations of the above and the like. Preferredtechniques of this nature include solvent casting, spin coating, webcoating, solvent spraying, dipping, fiber forming, ink jet techniquesand the like. In many cases, the solution is applied to a template, andthe desired component is obtained, after solvent elimination, by simplyremoving the block copolymer from the template. Such techniques areparticularly appropriate for forming simple objects such as sheets,tubes, cylinders and so forth.

One example of a solvent-based technique for forming a device or deviceportion can be found, in Example 3 of U.S. Pat. No. 5,741,331 toPinchuk. In this example, styrene/isobutylene copolymer is dissolved inthe amount of 6% solids (unless indicated otherwise, all percentagesherein are weight percentages) in tetrahydrofuran and the resultingsolution sprayed with an airbrush onto a rotating mandrel, which acts asa template. The environment is controlled during spraying so that thetetrahydrofuran evaporates between the sprayer and the mandrel, allowinga porous mat to be formed on the rotating mandrel. These samples arethen fully dried in air and removed from the mandrel. Such a techniquecan be used to form, for example, vascular grafts, stent-grafts,vascular patches, hernia patches, heart valve sewing rings, and thelike.

When forming devices or device portions containing a therapeutic agentusing solvent-based techniques, so long as the solvent is compatiblewith the therapeutic agent, the therapeutic agent can be provided in thecopolymer/solvent mixture, for example, in dissolved form or as aparticulate suspension. Such techniques allow the therapeutic agent tobe loaded concurrently with component formation.

If desired, the copolymer/solvent mixture can contain more than onesolvent (for example, one solvent appropriate for the block copolymerand a different solvent appropriate for the therapeutic agent). As aspecific non-limiting example, where paclitaxel is selected as a drugand where the copolymer is the triblockpolystyrene-polyisobutylene-polystyrene, a solution made from toluene,tetrahydrofuran, paclitaxel and the copolymer can be used.

In cases where the therapeutic agent is not provided at the same time asdevice or device portion formation, if desired, the therapeutic agentcan be loaded subsequent to component formation as discussed furtherbelow.

A coating is a preferred device portion that is frequently used inconnection with the present invention. For example, the copolymersdisclosed herein can be used to form coatings on medical device surfaces(e.g., internal or external surfaces). Such surfaces are formed from awide variety of materials, including glass, metals, polymers, ceramicsand combinations thereof.

Various techniques are available for forming coatings of the copolymeron surfaces of medical devices.

For example, coatings can be formed via thermoplastic processing, forexample, by co-extruding the coating along with a medical devicecomponent.

In a preferred technique, the copolymer is first dissolved in a solventthat is compatible with the copolymer, followed by application of thecopolymer solution to at least a portion of a medical device. Preferredtechniques include solvent casting, spin coating, web coating, solventspraying, dipping, ink jet and combinations of these processes. Ifdesired (for example, to achieve a desired coating thickness), suchcoating techniques can be repeated or combined to build up the coatedlayer to the desired thickness. Coating thickness can be varied in otherways as well. For example, in one preferred process, solvent spraying,coating thickness can be increased by modification of the coatingprocess parameters such as increasing flow rate, slowing the movementbetween the device to be coated and the spray nozzle, providing repeatedpasses, and so forth. In general the ultimate coating ranges from about0.5 micron to 50 microns in thickness, more preferably 2 to 30 microns.

If desired, a therapeutic agent of interest can be provided at the sametime as the copolymer coating, for example, by adding it to a copolymermelt during thermoplastic processing or by adding it to a copolymersolution during solvent-based processing as discussed above.Alternatively, it can be added after the coating is formed as discussedfurther below.

As previously noted, in some embodiments of the present invention, atherapeutic agent is provided after formation of the device or deviceportion. As an example of these embodiments, the therapeutic agent canbe dissolved in a solvent that is compatible with both the copolymer andthe therapeutic agent. Preferably, the coating or component is at mostonly slightly soluble in the solvent. Subsequently, the solution iscontacted with the device or device portion such that the therapeuticagent is loaded (e.g., by leaching/diffusion) into the copolymer. Forthis purpose, the device or device portion can be immersed or dippedinto the solution, the solution can be applied to the device orcomponent, for example, by spraying, and so forth. The device orcomponent can subsequently be dried, with the therapeutic agentremaining therein.

In several examples given above, the therapeutic agent is providedwithin a matrix comprising the copolymer of the present invention. Thetherapeutic agent can also be covalently bonded, hydrogen bonded, orelectrostatically bound to the copolymer. As specific examples, nitricoxide releasing functional groups such as S-nitroso-thiols can beprovided in connection with the copolymer, or the copolymer can beprovided with charged functional groups to attach therapeutic groupswith oppositely charged functionalities.

Alternatively, the therapeutic agent can be precipitated onto thesurface of a device or device portion. This surface can be subsequentlycovered with a coating of copolymer (with or without additionaltherapeutic agent) as described above.

Hence, when it is stated herein that the block copolymer is “loaded”with therapeutic agent, it is meant that the therapeutic agent isassociated with the block copolymer in a fashion like those discussedabove or in a related fashion.

As previously noted, block copolymers of the present invention can beused to form entire medical devices or various portions of such medicaldevices. Examples include the use of the block copolymers of the presentinvention (1) as a single device, (2) as a combination of devices, (3)as a single device portion (such as a device component or a devicecoating), (4) as a combination of device portions, and so forth.

The block copolymers can also be used in connection with furtherauxiliary materials or device portions to achieve a desired result. Suchauxiliary materials or device portions include binders, boundary layers,blending agents, and so forth.

For example, in some instances a binder may be useful for adhesion to asubstrate. Examples of materials appropriate for binders in connectionwith the present invention include silanes, titanates, isocyanates,carboxyls, amides, amines, acrylates hydroxyls, and epoxides, includingspecific polymers such as EVA, polyisobutylene, natural rubbers,polyurethanes, siloxane coupling agents, ethylene and propylene oxides.

It also may be useful to coat the copolymer of the present invention(which may or may not contain a therapeutic agent) with a layer with anadditional polymer layer (which may or may not contain a therapeuticagent). This layer may serve, for example, as a boundary layer to retarddiffusion of the therapeutic agent and prevent a burst phenomenonwhereby much of the agent is released immediately upon exposure of thedevice or device portion to the implant site. The material constitutingthe coating, or boundary layer, may or may not be the same copolymer asthe loaded copolymer.

For example, the barrier layer may also be a polymer or small moleculefrom the following classes: polycarboxylic acids, including polyacrylicacid; cellulosic polymers, including cellulose acetate and cellulosenitrate; gelatin; polyvinylpyrrolidone; cross-linkedpolyvinylpyrrolidone; polyanhydrides including maleic anhydridepolymers; polyamides; polyvinyl alcohols; copolymers of vinyl monomerssuch as EVA (ethylene-vinyl acetate copolymer); polyvinyl ethers;polyvinyl aromatics; polyethylene oxides; glycosaminoglycans;polysaccharides; polyesters including polyethylene terephthalate;polyacrylamides; polyethers; polyether sulfone; polycarbonate;polyalkylenes including polypropylene, polyethylene and high molecularweight polyethylene; halogenated polyalkylenes includingpolytetrafluoroethylene; polyurethanes; polyorthoesters; polypeptides,including proteins; silicones; siloxane polymers; polylactic acid;polyglycolic acid; polycaprolactone; polyhydroxybutyrate valerate andblends and copolymers thereof; coatings from polymer dispersions such aspolyurethane dispersions (BAYHDROL®, etc.); fibrin; collagen andderivatives thereof; polysaccharides such as celluloses, starches,dextrans, alginates and derivatives; and hyaluronic acid.

Copolymers and mixtures of the above are also contemplated.

A preferred polymer is polyacrylic acid, available as HYDROPLUS® (BostonScientific Corporation, Natick, Mass.), and described in U.S. Pat. No.5,091,205, the disclosure of which is hereby incorporated herein byreference. In a most preferred embodiment of the invention, the polymeris a copolymer of polylactic acid and polycaprolactone.

It is also possible to form blends by adding one or more of the above orother polymers to the block copolymers of the present invention.Examples include the following:

-   -   Blends can be formed with homopolymers that are miscible with        one of the block copolymer phases. For example, polyphenylene        oxide is miscible with the styrene blocks of        polystyrene-polyisobutylene-polystyrene copolymer. This should        increase the strength of a molded part or coating made from        polystyrene-polyisobutylene-polystyrene copolymer and        polyphenylene oxide.    -   Blends can be made with added polymers or other copolymers that        are not completely miscible with either of the blocks of the        block copolymers of the present invention. The added polymer or        copolymer may be advantageous, for example, in that it is        compatible with another therapeutic agent, or it may alter the        release rate of the theraputic agent from the block copolymers        of the present invention (e.g.,        polystyrene-polyisobutylene-polystyrene copolymer).    -   Blends can be made with a component such as sugar (see list        above) that can be leached from the device or device portion,        rendering the device or device component more porous and        controlling the release rate through the porous structure.

The therapeutic-agent-loaded block copolymers are appropriate for anumber of administration avenues including insertion or implantationinto the body. Where the block copolymers are to be inserted orimplanted for an extended period of time, biocompatibility is ofconcern.

The release rate of therapeutic agent from the therapeutic-agent-loadedblock copolymers of the present invention can be varied in a number ofways.

Examples include:

-   -   varying the molecular weight of the block copolymers,    -   varying the specific constituents selected for the elastomeric        and thermoplastic portions of the block copolymers and the        relative amounts of these constituents,    -   varying the type and relative amounts of solvents used in        processing the block copolymers,    -   varying the porosity of the block copolymers,    -   providing a boundary layer over the block copolymer, and    -   blending the block copolymers of the present invention with        other polymers or copolymers.

As noted above, the block copolymers used in connection with the presentinvention are endowed with good biocompatibility. The biocompatibilityof polystyrene-polyisobutylene-polystyrene copolymers according to anembodiment of the invention is demonstrated below in connection withExample 6.

The invention is further described with reference to the followingnon-limiting examples.

EXAMPLE 1 Block Copolymer Synthesis

A styrene-isobutylene-styrene block copolymer is synthesized using knowntechniques. As is well known by those versed in the art of cationicchemistry, all solvents and reactants must be moisture, acid andinhibitor-free. Therefore, it may be necessary, depending upon the gradeof material purchased, to distill these chemicals or flow them throughcolumns containing drying agents, inhibitor removers and the like, priorto introducing them into the reaction procedure.

Assuming that all solvents are pure and moisture- and inhibitor-free,styrene is added to a dried, airtight styrene mixing tank. The tank isinitially chilled to between −19° C. (the condensation point of methylchloride) and −31° C. (the freezing point of pure styrene) using liquidnitrogen or other heat transfer media, whereupon methyl chloride gas iscondensed and added. Next, di tert-butyl-pyridine is mixed with hexanesand added to the styrene tank, followed by flushing with furtherhexanes. Isobutylene is then added to the styrene tank, followed bysufficient hexanes to bring total hexane weight in the styrene mixingtank to the desired amount. The temperature is then brought to about−70° C. and maintained at that temperature until used.

Hexanes are discharged into a dried, airtight reactor, containingcooling coils and a cooling jacket. The reactor with the hexanes iscooled with liquid nitrogen or other heat transfer media. Methylchloride is condensed into the reactor by bubbling the gas through thecooled hexanes. A hindered t-butyl dicumyl ether, dimethyl phthalate anddi tert-butyl-pyridine are added to the reactor, flushing with hexanes.Isobutylene is charged and condensed into the reactor by bubbling thegas thought the cooled solvent system. The temperature is maintained atabout −70° C. After the isobutylene is added to the reactor, titaniumtetrachloride is then charged to the reactor, flushing with hexanes, tostart the reaction. After the appropriate amount of isobutylene has beenadded, the reaction is allowed to continue for 15 to 30 min.

The contents of the styrene tank (prechilled to −60 to −70° C.) are thenadded to the reactor, maintaining the reactor at a temperature of about−70° C. After adding all the contents of the styrene tank, the contentsof the reactor are allowed to react an additional 15 to 45 minutes,whereupon the reaction is quenched with methanol.

The reactor is then allowed to warm to room temperature, while beingaware of any pressure increases, and the methyl chloride is removed fromthe reactor by boiling it and condensing it into a chilled collectiontank. An additional amount of hexanes, or other solvent, such astetrahydrofuran or toluene is added to the reactor to replace theremoved methyl chloride. These additional solvents are used tosolubilize the polymer to enable it to be drained out of the reactor, asotherwise the polymer becomes too thick to readily flow. The copolymersolution from the reactor is then precipitated in methanol (equal inweight to the initial copolymer/hexanes to be coagulated). Theprecipitated polymer is then poured into a sieve, the polymer removedand dried in a vacuum oven for at least 24 hours at approximately 125°C. under full vacuum.

EXAMPLE 2 Solvent-based Coating Technique

An example of a solvent-based technique for coating a medical device,such as a stent, follows. As always, the solvent system selected for usein such a procedure will depend upon the nature of the block copolymerand therapeutic agent selected. In the case of apolystyrene-polyisobutylene-polystyrene triblock copolymer andpaclitaxel therapeutic agent, a preferred solution is one containing (1)between 0-94%, preferably 94%, toluene, (2) between 5%-99%, preferably5%, tetrahydrofuran and (3) 1% copolymer and paclitaxel combined. Such asolution can be provided by (1) mixing the paclitaxel andtetrahydrofuran, (2) adding the copolymer, (3) adding the toluene, (4)thorough mixing (e.g., overnight), and (5) filtering (e.g., through afine filter such as a 0.22 micron filter). The solution of interest canthen be placed in a syringe pump, and the fluid can be fed to a spraynozzle. The component of interest (e.g., catheter, catheter balloon,stent, stent graft, vascular graft, etc.) can be mounted onto a holdingdevice parallel to the nozzle and, if desired, rotated (e.g., at 45 RPM)to ensure uniform coverage. Depending on the spray equipment used,either the component or spray nozzle can be moved while spraying suchthat the nozzle moves along the component while spraying for one or morepasses. For instance, a nozzle pressurized at 15 psi for a flow rate of6.3 mL/hr solution (polystyrene-polyisobutylene-polystyrene copolymer,paclitaxel, toluene and tetrahydrofuran), provided at a distance of 1.0inch from the component and moved relative to the component between0.3-0.5 mm/sec can produce a thickness of 2.5 to 4.0 microns.

EXAMPLE 3 Solvent-based Coating Technique

In another preferred process, a solution like that above containing (1)between 0-94% toluene, (2) between 5-99% tetrahydrofuran and (3) 1%polystyrene-polyisobutylene-polystyrene copolymer and paclitaxel issprayed with an airbrush onto a rotating medical device component, suchas a stent. The environment is controlled during spraying so that thetetrahydrofuran and toluene evaporates between the sprayer and thecomponent, allowing a porous mat loaded with a therapeutic agent to beformed on the rotating component. Spraying is stopped when the desiredcoating thickness is achieved.

EXAMPLE 4 Drying Process

After a component or layer has been formed using one of the abovesolvent-based techniques, the component or layer can be dried, forexample, by placing it in a preheated oven (e.g., for 30 minutes at 65°C., followed by 3 hours at 70° C.).

EXAMPLE 5 Release Characteristics

The release rate can be varied by varying the relative amounts of drugand copolymer. FIG. 1 illustrates release rate as a function of time forNIR stents coated with polystyrene-polyisobutylene-polystyrene copolymerand paclitaxel in varying ratios. The coating formulations were madewith 94% toluene and 5% tetrahydrofuran, with the remaining 1% of theformulation being made up of paclitaxel and styrene-isobutylenecopolymer in respective relative amounts of 35%-65%, 32.5%-67.5%,30%-70%, 25%-75%, 22.5%-87.5%, 20%-80% and 17.5%-83.5% with anequivalent total coating weight. Coating thickness was about 16 microns.The release rates in FIG. 1 range from a relatively rapid release inconnection with the highest paclitaxel value (35%) to a relatively slowrelease at the lowest value (17.5%).

EXAMPLE 6 Biocompatibility

For this investigation, the following are provided: (1) a bare stainlesssteel NIR (Medinol, Israel) stent; (2) a NIR stent with a coating oftraditional “biostable” polycarbonate urethane polymer (Chronoflex AL,CardioTech Inc., Woburn Mass.); (3) a NIR stent with a coating of atraditional “biodegradable” copolymer of polylactic acid (“PLA”) andpolycaprolactone (“PCL”) (Birmingham Polymers, Birmingham, Ala.); and(4) a NIR stent with a coating ofpolystyrene-polyisobutylene-polystyrene copolymer in accordance with thepresent invention.

These stents were implanted in a porcine coronary artery. After 28 days,the stent was harvested from the animal and examined for both stenosis(neointimal thickening) and inflammation. Stenosis was measuredangiographically. Inflammation was measured by blinded observers basedon microscopic inspection of sections retrieved from the porcine artery.Inflammation values of 1 to 4 were assigned, with 1 representing theminimal inflammation and 4 representing maximal inflammation. Theresults are presented in the following table:

Coating Stenosis (%) Inflammation None (Bare Stent) 43 ± 7 2.6 ± 0.7Polycarbonate urethane  75 ± 15 3.9 ± 0.8 Polystyrene-polyisobutylene-47 ± 9 1.5 ± 0.5 polystyrene copolymer PLA/PCL copolymer — —

As can be seen from this table, stenosis and inflammation weresignificantly higher with the stents coated with traditionalpolycarbonate urethane polymer than was observed than with the barestent or with the stents coated withpolystyrene-polyisobutylene-polystyrene copolymer.

FIGS. 2A, 2B, 2C and 2D show representative histology of the sectionsfrom the stented arteries. The extent of inflammation and neointimalthickness was much more pronounced in FIG. 2C (appearance of the vesselassociated with the traditional “biostable”polyurethane-carbonate-coated stent) and FIG. 2D (traditional“biodegradable” PLA/PCL copolymer), than in FIG. 2A (bare stent) or FIG.2B (polystyrene-polyisobutylene-polystyrene coated stent).

Although various embodiments are specifically illustrated and describedherein, it will be appreciated that modifications and variations of thepresent invention are covered by the above teachings and are within thepurview of the appended claims without departing from the spirit andintended scope of the invention.

1. A coated medical device comprising: an intravascular or intervascularmedical device; and a coating over at least a portion of saidintravascular or intervascular medical device, said coating comprising abiocompatible block copolymer comprising one or more elastomericpolyolefin blocks and one or more thermoplastic blocks, wherein theamount of polyolefin blocks ranges from between 95 and 45% mol of theblock copolymer.
 2. The coated medical device of claim 1, wherein saidone or more thermoplastic blocks are selected from vinyl aromatic blocksand methacrylate blocks.
 3. The coated medical device of claim 1,wherein said block copolymer is of the formula X-(AB) n, where A is anelastomeric block, B is a thermoplastic block, n is a positive wholenumber and X is a catalyst seed molecule.
 4. The coated medical deviceof claim 3, wherein A is a polyolefin block and B is a vinyl aromaticblock or a methacrylate polymer block.
 5. The coated medical device ofclaim 4, wherein B comprises one or more monomers selected frommethylmethacrylate, ethylmethacrylate and hydroxyethyl methacrylate. 6.The coated medical device of claim 4, wherein A is a polyolefin block ofthe general formula —(CRR′—CH2)n-, where R and R′ are linear or branchedaliphatic groups or cyclic aliphatic groups and wherein B is a vinylaromatic polymer block.
 7. The coated medical device of claim 6, whereinsaid polyolefin block comprises an isobutylene monomer and wherein saidvinyl aromatic polymer block comprises one or more monomers selectedfrom styrene and α-methylstyrene.
 8. The coated medical device of claim6, wherein the molecular weight of the block copolymer ranges from80,000 to 300,000 Daltons.
 9. The coated medical device of claim 6,wherein the molecular weight of the polyolefin blocks ranges from 60,000to 200,000 Daltons and the molecular weight of the vinyl aromaticpolymer blocks ranges from 20,000 to 100,000 Daltons.
 10. The coatedmedical device of claim 1, wherein said intravascular or intervascularmedical device is selected from a balloon, a stent, a shunt, a catheter,a stent graft, a vascular graft, a vascular patch, a shunt and a filter.11. The coated medical device of claim 1, wherein said coating rangesfrom 0.1 to 40 microns in thickness.
 12. The coated medical device ofclaim 1, wherein said coating is not a barrier layer.